Grand Rounds 4.44 at GruntDoc!

Thanks to GruntDoc for the effort put into hosting this week's Grand Rounds 4.44. I am grateful that he included my recent post on Amniocentesis is Not Without Risk.

Admittedly, it is a long post, but it tells a story. I may be wrong, but I get the sense that the decisions being made by a couple of the featured readers are based on incomplete information and/or biased presentation of the same. (And, for our physician readers, I am not ruling out the possibility that certain patients hear what they want to hear!). That frustrates me because there is no one more vulnerable to that than pregnant women and their families.

It is sometimes hard to present the advantages/disadvantages and risks/benefits of the screening tests that are available during pregnancy without keeping our own feelings out of the equation, but an honest effort must be made to do so. That is especially true when the outcome of such a screening test might lead to an invasive diagnostic study such as an amniocentesis that could put the pregnancy at risk, albeit the risk is small. I am careful to tell patients that, they alone can make a decision with which they are most comfortable - a decision I cannot and will not make for them. In fact, I go so far as to tell them that I don't care what decision they make and that I don't care what they do with the information they may get from the procedure! But, to make that decision, they deserve to have balanced information with some responsibility on the part of the provider that they actually understand the information they are given. In the end, all we can promise is that if their choice is to proceed with an amniocentesis, we will do the best we can to make it, technically, the safest procedure possible.

Labels: amniocentesis, first trimester screening

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Amniocentesis is Not Without Risk

Occasionally, a series of comments are left that leave me feeling quite disturbed. Included below is such a series received over the past few weeks, and to which I responded, that tell a story all by themselves. Please read all the way to the end and you will understand why they have been linked together…

• At Wed Jul 16, 04:42:00 PM 2008, anonymous said…

Dear Dr T
Just found this site and took a lot of encouragement from it. I an agonizing over the amniocentesis and have been for the past 4 weeks. I am now week 20 and this is my last chance to have it. My age is 42. I got pregnant very quickly and my (first trimester screening) test results were… overall risk 1/1250 for Down syndrome. I decided not to have amnio based on this and am now so anxious about the prospect of Downs I feel quite ill with the worry. My local hospital claims their amnio miscarriage rate is between 0.5 and 1.0 per cent. I am torn between not getting pregnant again given my age and driving myself ill with stress of not knowing for sure.

Many thanks.

• At Fri Jul 18, 05:23:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To anonymous July 16:
I cannot make the decision for you, but I will tell you four things: 1) You got a GREAT test result for your age; 2) The quoted risk of the amnio at your hospital is 5 to 10 times greater than the chance that this baby has Down syndrome; 3) If you lose the baby as the result of the amnio, odds are you will be losing a NORMAL baby; and 4) If you get pregnant again, the odds are about 20-25 times greater than your current risk that you will have a chromosomally abnormal baby! But, the final choice is yours and you have to live with whatever decision you make, so best wishes!
Dr T

• At Thu Jul 17, 11:24:00 AM 2008, agoura said…

Hi Dr.
I am 30 yrs old and this is my 1st pregnancy- I am 20 weeks along. I have had an ultrasound at 18 weeks and was called in for genetic counseling because they saw a variation - an echogenic focus was found in the left side of the heart. Although they note it's a "soft marker" for Downs Syndrome my Dr. recommended I have an amnio. They said my rate of having a baby with Down Syndrome (from my APF testing) was 1 in 2600 - but now because of these new findings my ratio has gone up to 1 in 1445. I know it seems very unlikely - I guess my question to you is- how many children in your experience have you seen this echogenic focus and they actully turn out to be healthy babies versus babies being born with a birth defect. The baby (i was told) was very healthy and growing as it should, and all my testing came back with great results - this has been the only bump in the road. I am going ahead with the amnio- do you think I should really be worried about miscarrying OR having a baby with D.S?
Thanks for your advice!

• At Fri Jul 18, 05:02:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To agoura:
Almost ALL babies with echogenic intracardiac foci (EIFs) are NORMAL. In fact EIFs are very common and are present in about one-third of all Asian women. An EIF alone is a terrible reason to do an amniocentesis and I never recommend that to my patients - especially if they have a risk assessment as good as yours. The risk of the amnio is still three to five times greater than the chance of having a chromosomally abnormal baby in your case. And, think about this - if you lose the baby as the result of the amnio, the overwhelming odds are that the baby you lose would be chromosomally normal. Even factoring in the EIF (which I am truly loathe to do), the chance of having a baby with Down syndrome is still much less than your age alone risk which happens to be about 1 in 840! And, when you get pregnant again, the risk will be even higher. But, the final choice is yours. Good luck!
Dr T

• At Thu Jul 17, 04:45:00 AM 2008, Anonymous said…
Hi Dr, I am writing from Australia and am 18 weeks pregnant. My 12 week scan gave me a score of 1:1010 for Down Syndrome... I will be 38 when the baby is delivered and am constantly filled with anxiety about not having an amnio. I booked in for one but then cancelled as no one had advised it. What sort of reassurance can I get from the 19 week scan and can I still have an amnio? What should I be asking them to look for? I understand I should have faith in the score, but I could be the 'one'. Is there less chance of a miscarriage having an amnio at 19 weeks? Thanks so much for your time.

• At Fri Jul 18, 04:56:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To anonymous from Australia:
The test result is what it is and in your case it is a very good result. Your ‘age alone’ risk for Down syndrome in first trimester is 1 in 100 – ten times more than your calculated risk assessment – and that is information based on your pregnancy and not just a whole population of 38 year old women. It is much more reliable than counseling you based on age alone. The 18-20 weeks scan, if all is normal, will further reduce your risk more than 50% (range 50-90%). You can certainly wait until then to do the amnio and most good genetic labs can give you a result by fluorescent in situ hybridization (FISH) regarding many common chromosomal abnormalities (including Down syndrome) in 72 hours or less. The final choice regarding the amnio is yours, but remember this, if you are the 1 in 200 to 1 in 500 person who LOSES their baby from the amnio, odds are you will lose a perfectly NORMAL baby! Good luck.
Dr T

• At Fri Jul 11, 02:42:00 AM 2008, katja said…

Hi Dr T,
I had an amnio done 3 days ago, the procedure went fine and I'm ok, just some mild cramping. When are you considered to be 'safe' from miscarriage due to the amnio? My doctor said the first 48 hrs are crucial, and then some can have an infection up to a month after the procedure. Does that seem right to you? I read some stories about women losing fluid and having infections even a month later. What are the reasons for that infection? Do the membranes close up themselves or is it possible the hole doesn't close up at all?

Thank you, Kat

• At Sat Jul 12, 08:53:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Kat:
The first 48-72 hours are critical from the standpoint of rupturing membranes following an amnio based on the needle entry alone. We use very thin needles and the hole generally closes up completely within that period of time. But the risk of infection does extend out about a month and that is the most common cause of delayed rupture of membranes. Early delivery is almost inevitable if you do develop an intrauterine infection under those circumstances – no antibiotic regimen will help. Fortunately, infection is remarkably rare following amniocentesis.
Dr T

• At Fri Jul 18, 12:04:00 PM 2008, Chris said…
I had an amniocentesis at 16 weeks. I did not have any real cramping, fever, spotting, leaking of fluid after the amnio. At my 20 weeks ultrasound, I was told the baby had died in utero. The doctors blamed it on the amnio. The amnio showed that there were no chromosomal defects. If I lost the baby due to an infection, wouldn't I have had symptoms.

Also, if the baby hits the side of the needle, could this cause fetal demise and if it could, how long would it take for the fetus to die?

• At Fri Jul 18, 06:48:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Chris July 18:
I am so sorry for your loss. But others should know that an amniocentesis is a procedure that does carry some risk, and so I hope you don’t mind if I include your comment in a post that addresses this subject.

It is unusual for a baby to die from a needle stick alone. Inadvertent laceration of the umbilical cord would be a more common cause of fetal death. When babies are lost as the result of an infection, I have been truly amazed by how much infection can be 'hidden' inside the uterus without the mother having a fever, pain, or even an abnormal white blood count. Sometimes the only sign is rupture of membranes and uterine cramping. Again, I am so sorry for your loss, but please let us know what you find out. I know it is hard, but thank you for sharing your story. Amniocentesis does carry some risks.
Dr T

Labels: amniocentesis, echogenic intracardiac foci, first trimester screening

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First Trimester Screening and Twins

Below is a series of excellent questions and my responses related to first trimester screening from a woman who has an IVF pregnany and twins...

• At Fri Jun 27, 06:53:00 AM 2008, Anonymous said…

Hi: How reliable is first trimester screening (FTS) in twins pregnancy? I was told it is not and some said it is. We are trying to make a decision if we will pursue chorionic villus sampling (CVS). I am 36 and I would be 1 month away from 37 when it is my due date. I am now 11 weeks almost 12. I did the FTS and the ultrasound looks good. The genetic counselor said the blood test will not be as accurate as in singleton pregnancy. The spaces on the necks (nuchal translucencies) on both babies are normal and look good. We conceived using IVF (1st cycle). It is unexplained infertility. I had natural pregnancy once but miscarried during 7-8 weeks (no heart beat detected). No family history of birth defect on either side. I am Asian if this matters and my husband is white (British/ French). I really appreciate your opinion. Thank you.

• Tue Jul 01, 01:05:00 PM 2008, Anonymous said…
Dr. T.
I left comment earlier on 6/27 about reliable in FTS in twin. I just got the test results for FTS:

IVF/ICSI cycle
36 yrs (asian) weight 165 lbs
Gest Age: 11.3 wks
IDDM: no DS HX: NO
NT: 1.3 mm and 1.5 mm
CRL: 49.3mm and 48.3 mm
Nuchal Translucency: 1.08 MoM/ 1.25 Mom
PAPP-A: 3.00 MoM
hCG - 1.36 Mom

Down Syndrome: Screening Risk 1:660 Age Risk 1:130
Risk Cutoff: 1:50
Trisomy 18: Screening Risk - can't accurately estimated in twin
Age Risk 1:470
Risk Cutoff: 1:100

We were told by the genetic counselor and another doctor who does CVS that our position is good base on the FTS result. We would do amniocentesis at 16 weeks, but if there would be an unfortunate result, would that be too late to do selective reduction which it could be 18 weeks by the time we get the result?

I would appreciate any comment based on your expertise. These tests are very confusing and driving us crazy. Thank you so much for having such an informative blog for all Moms-to-be.
W.

• At Tue Jul 01, 05:51:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To W: Those are very good first trimester results. Personally, I have found combined first trimester screening (NT measurements plus maternal serum markers) to be very helpful in twins. Below is an abstract from a recent article that gives you some idea of its value. I would suggest an MSAFP only (and perhaps another ultrasound) at 16 weeks and then a good genetic sonogram at 18-20 weeks. If all that checks out fine, you probably do not need to have any invasive procedure done and with those first screening results, we would not ordinarily recommend a CVS at all. Of course, regardless of what we suggest, the final choice is yours!

It is not too late to do selective reduction at 18 weeeks or even later, but the risks do go up with gestational age. If you have an amnio done and you are seriously considering selective reduction if one of the babies is chromosomally abnormal, consider having a FISH study done from which you can get a result back in about 72 hours. I am NOT recommending it in your case at this time, but if you elect to proceed with the amnio,that is an option to consider.

Best of luck and please let us know how things turn out. By the way, at the time of the genetic sonogram, ask your doctors to evaluate your cervical length as well! Infertility patients are notorious for having unsuspected cervical incompetence, especially with multiple gestations!

Thanks for reading and good luck to you for the rest of the pregnancy!
Dr T

*******************************************************************************

Chasen, et al., First-trimester risk assessment for trisomies 21 and 18 in twin pregnancy. Am J Obstet Gynecol 2007;197:374.e1-3.

OBJECTIVE: Our objective was to describe performance of first-trimester combined risk assessment in twin pregnancies. STUDY DESIGN: Twin pregnancies that underwent risk assessment in our ultrasound unit from 2003-2006 were included. Adjusted risks for trisomies 21 and 18 that were based on age, nuchal translucency (NT), and biochemistry were provided for each twin. Detection rates for Down syndrome and trisomy 18 were calculated for age/NT, and age/NT/biochemistry at a screen-positive rate of 5% of pregnancies. RESULTS: Five hundred thirty-five pregnancies were included. Median maternal age was 34 years, with 47% of women > or = 35 years old. There were 7 fetuses in 6 dichorionic pregnancies with Down syndrome and 3 fetuses in 3 pregnancies with trisomy 18. For a 5% false-positive rate, age/NT identified 83.3% of Down syndrome and 66.7% of Trisomy 18 pregnancies. Adding biochemistry resulted in 100% detection rates for both conditions. CONCLUSION: The addition of biochemistry may enhance first-trimester risk assessment in twin pregnancies. Further studies with larger numbers of affected pregnancies are needed.

Labels: amniocentesis, chorionic villus sampling, first trimester screening, FISH

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Invasive Diagnostic Testing after Reassuring First Trimester Screening for Aneuploidy?

Attached is a comment from a reader who has written to me before because of a history of recurrent early pregnancy losses. She is now pregnant, has successfully gotten through first trimester, and has had very reassuring combined risk assessment for aneuploidy. She is now wrestling with the decision regarding whether or not she should undergo an amniocentesis for fetal chromosomal analysis anyway, mostly because of her age. In the end, she will have to make that decision herself, but in my response, I offer a perspective, occasionally, overlooked, to her and to others who are facing this decision...

Dr. T - I wrote to you a few months ago on your recurrent loss blog regarding my two 2007 1st trimester losses - I followed your advice to see a good RE (reproductive endocrinologist), we found impaired glucose tolerance, I started metformin, and I am happy to report that I am 15 1/2 weeks pregnant with what seems to be a healthy baby! So, thanks for that.

Here's my new question: I just turned 39. I had a NT done, and my risk for Downs is 1/2000 and my risk for Trisomy 18 is 1/3700 - which is reassuring. I scheduled an amnio anyway, because I am 39, and because of the possibility of the chromosomal problems with my lost pregnancies last year. Now, I am a week away from the amnio, and I am getting paranoid about the risk from the amnio of losing this baby. What I don't quite understand is how a history of previous losses impacts the risk of amnio. Does it make a difference if your previous losses were not spontaneous miscarriages, but missed ones? I was ok with my decision to have an amnio until yesterday, and now I can't get past the thought that something bad might happen. I know that my doctor doesn't care either way if I do the test or not, but I don't want to talk myself out of (or into) something if I am being overly cautious. Thanks in advance.
Liz
Tue Jan 22, 09:25:00 AM 2008


Kenneth F. Trofatter, Jr., MD, PhD said...

To Liz Jan 22: Liz, I am not going to tell you what to do. But, let me put this in perspective. The risk of the amniocentesis in experienced hands is still about twice that of your a priori risk for having a baby with Down syndrome or trisomy 18 (and probably several other chromosomal abnormalities as well) based on your first trimester screening results. In less experienced hands, the amniocentesis risk can be 10 times your first trimester screening risk! With those odds, if you did happen to be the 1 in 1000 (or 1 in 200) who lost their baby as the result of the amniocentesis, the overwhelming odds are that you will lose a completely NORMAL baby.

You are doing very well, you have been through a lot to get to this point, odds are this baby is normal, and you are 39 years old. You may not have many more opportunities if this one is lost. One option to consider, rather than jumping into the amniocentesis now, is to simply have a genetic sonogram done at 18-20 weeks. If that is normal, your a priori risk (based on the first trimester screening results, NOT your age) is reduced by at least another 50% (I generally quote folks 60-80%). So, answer me this...how does a 1 in 4,000 risk sound to you? If something really suspicious is seen at that point such as poor fetal growth, congenital heart defect, or a major marker for aneuploidy (and I am NOT talking about an echogenic intracardiac focus, or even a choroid plexus cyst alone), you could still opt for the amniocentesis with a FISH (fluorescent in situ hybridization) analysis for the more common types of chromosomal abnormalities. This can give you highly reliable results within 72 hours. Using first trimester screening, coupled with this approach, we have not missed a chromosmal abnormality in more than three years, nor lost a baby from an amniocentesis. By the way, CONGRATULATIONS! Again, best wishes to you and please let us know how you do with the pregnancy!
Dr T

Tue Jan 22, 05:27:00 PM 2008

Labels: amniocentesis, aneuploidy screening in first trimester

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Chromosomal Abnormalities and Multiple Gestations - 2

…After talking with one of our genetic counselors, I went back into the room (see previous post). By this time, they had both used some tissues and were ready to talk more. They agreed to see the counselor and we walked across the hall to her office. (We are blessed with great genetic counselors). Over the course of 30-40 minutes, she explained ‘nondisjunction’ as the cause of increased risk for chromosomal abnormalities with advancing age, the actual risk for aneuploidy in midtrimester at age 40 in singleton (1/75 for Down syndrome; 1/44 for all aneuploidy) and twin pregnancies (about twice these risks that one of the babies will be abnormal in twins from different eggs), the diagnostic procedures that could be done to confirm the diagnosis, the benefits of knowing if the baby has a chromosomal abnormality with regard to decision-making during and after the pregnancy, and specific information with regard to the presumptive diagnosis of trisomy 18.

The patient was then asked if she wanted an amniocentesis and both she and her husband agreed that, based on what we had told them, they needed to know if the baby had a chromosomal problem, even though “we only want the procedure done on the baby that appeared abnormal.” (I wish I could accurately portray here the skepticism that was conveyed in the way the word “appeared” was inflected, but never being one to take away all hope, I just let it slide). I told them that under the circumstances, that was a very reasonable request. The normal ‘growth and appearance’ of the other baby probably reduced her risk for a chromosomal abnormality by as much as 90%. The procedure was then explained to them, including the small risks, and a consent was signed. As I always do under these circumstances, I made it quite clear that if the baby was lost following the amniocentesis, it would be much more likely due to the condition of the baby rather than to the procedure itself. She nodded that she understood. When asked if they had any questions, the only query was the inevitable, “I heard these things are awful…does it really hurt.” Welcoming the query, I gave her my patented reply that “it is going to be the most painful thing you have ever been through in your entire life and the large nurses in the room are here to hold you on the table.” She smiled and we did the procedure without any complications.

The amniotic fluid was sent for fetal karyotype studies by both fluorescent in situ hybridization (FISH) and routine culturing techniques. She was offered the FISH and told that a ‘presumptive diagnosis’ could be back within 48-72 hours and the routine culturing studies (results available in 10-14 days) could be used to confirm the FISH results and/or identify other chromosomal abnormalities not detected by the FISH assays; and, she readily accepted this approach. We would notify her directly as soon as any results were back and arrange for her to return to discuss the findings and options for follow-up depending on the diagnosis and her own needs.

A few days later, unfortunately, but as expected, the baby’s karyotype by FISH came back as 47XY,+18 (trisomy 18). When she was called, her immediate response was, “Some friends told me the FISH has lots of false-positives, so the baby could still be all right, right? Don’t we have to wait for the final results of the cultures?” Again, not to mince words, I told her that it was very unlikely the cultures would change the FISH results. In fact in 20 years, I have not seen a single FISH diagnosis of aneuploidy be overturned by the culture technique (although I have seen ‘negative’ FISH studies in circumstances where the final results demonstrated a chromosomal abnormality not included in the FISH profile). The silence that followed was deafening, and the crying that followed that was heartbreaking, but when she finally asked between tears, “Where do we go from here?,” I knew we were going to be alright. “Why don’t you come back to talk with us when you are ready; we’ll work you in on a moment’s notice if necessary…”

Labels: amniocentesis, aneuploidy, chromosomal abnormalities, FISH, trisomy 18, twins

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Fetal Cystic Hygromas in First Trimester

Today I received another comment to a post I wrote awhile back on aneuploidy (chromosomal abnormality) from a reader who has a first trimester baby that was found to have a cystic hygroma. With the growing acceptance of first trimester screening for aneuploidy as a 'standard of care' in the U.S. (the rest of the world discovered this several years back!), we are identifying more and more fetal abnormalities early in pregnancy. Since this too is becoming a topic of widespread general interest, I thought it would be worthwhile to highlight three of the comments/questions that were addressed to me so that other readers can hear about real situations and have a point of reference to current thought on this important issue. With apologies to the readers who left the original comments, I have modified the comments as necessary to the best of my understanding so that other readers will more easily understand their concerns...


Sat Jun 09, 09:10:00 AM 2007, Laura said:
My name is Laura and I am 24 years old. Me and my husband went for our first 12 week ultrasound scan a couple of days ago and to our shock we were told that our unborn child has a cystic hygroma, which we are told is fluid underneath the skin at the back of the babies neck (the nuchal translucency) measuring 6 mm. We are devasted at this news because we are told the outlook is not good. It is our first pregnancy and it has taken us so long to get pregnant due to my polycystic ovaries, it just makes it so much harder to deal with. We decided to have a CVS (chorionic villus sampling). They took a biopsy from the placenta which they are now going to test. We should have the rapid test results for Down syndrome, Turner syndrome, and Edwards syndrome by 13th June. We are praying that they will come back clear. They are also going to do routine chromosomal studies to look for other chromosomal abnormalities that are not detected by the rapid test. They said if all the tests are normal, and if the fluid drains away by 18-20 weeks we may have a chance. Its just so hard to understand how some fluid behind the neck could indicate these sort of problems. I am only 24 years old, and so is my husband. We are young, fit and eat a very healthy diet, it just seems so unfair. Do you have any idea of our odds. What is the percentage of babies that do get over this? Have you had any success stories that could give us some hope? Thank you for your time and we hope to hear back soon. Laura

Tues Jun 12, 09:10:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD responded:
I know this is hard, especially in a first pregnancy you have had so much trouble getting to because of your polycystic ovary syndrome. Unfortunately, finding the cystic hygroma in first trimester is associated with a very high risk for a baby that has a chromosomal abnormality, most often Down syndrome (trisomy 21 = 47,+21)), Turner syndrome (45XO,missing one sex chromosome), or Edwards syndrome (trisomy 18 = 47,+18). Sometimes cystic hygromas are associated with gene defects and not chromosomal abnormalities per se. Examples of the latter include Noonan syndrome, Roberts syndrome, polysplenia syndrome, multiple pterygium syndrome, and others. At times the baby has no chromosomal abnormality or obvious genetic condition. Under these circumstances, there is an increased risk for a major heart abnormality as an underlying cause, although we do not entirely understand why babies develop cystic hygromas under these circumstances. The prognosis for the baby depends on what problems the baby has, chromosomal, genetic, and/or associated structural. If the baby has no chromosomal abnormality and does not go into heart failure (develop hydrops fetalis), it may well survive the pregnancy. If no syndromic problems, chromosomal mosaicism, or gene defects are discovered after delivery, the baby may have a reasonable chance at doing well. Your doctors will discuss this more with you after they get your test results back. At that point (if they haven't already), they will probably refer you to a genetic counselor to get more information. Good luck to both of you and thank you for reading. By the way, it is highly unlikely that anything you have any control over caused this to happen. If you will, let me know what the tests show and how the pregnancy turns out...


Sun June 24 11:50 AM 2007, Anonymous said:
Dr. Trofatter, I am 41 year old with a 14 week pregnancy. Due to AMA (advanced maternal age) I elected to have a nuchal translucency (NT) scan done and the perinatologist found a large cystic hygroma; I was told extremely large 180mm3 and the doc was not optimistic. He performed CVS that day and we just recieved news that the FISH results were normal. Because there are no genetic defects, I was told we are looking at heart abnormalities, probably severe. My husband and I are deciding whether to terminate but the normal chromosome results makes this decision difficult. I have been doing research on the web for days now and I find myself unable to take care of myself and my family. I am reading the prognosis is poor and if I wait beyond 18 weeks I cannot terminate the pregnancy in my state. My question is can or should I get repeated ultrasound hoping the hygroma goes down and how often is an ultrasound indicated for this? Will the hygroma go down all at once or little by little or how much at a time? Please help me. Thank you

Tues June 26 02:47 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD responded:
Large cystic hygromas have a very poor prognosis, even if the baby is chromosomally normal. Even if the FISH results are reassuring at this point, your baby could have a chromosomal abnormality that was not detected by FISH. Your doctors have counseled you that this baby could also have a major cardiac malformation or other major abnormality that impedes return of fluid and lymph to the heart, even in the absence of a chromosomal abnormality. If the baby develops a condition called hydrops fetalis, this would indicate heart failure for any reason and the prognosis is usually fatal at that point. If the baby is chromsomally normal, has no other genetic or syndromic problem, has no major heart abnormality, and resolves the cystic hygroma, it may well survive and do quite well in the long term. I would recommend another ultrasound before 18 weeks. In many cases, major heart and other abnormalities can be identified by that time and you will have the final results of the fetal chromosome studies back to guide your decision. I am so sorry. It is difficult to be in your situation. If you have not seen a specialist in Maternal-Fetal medicine, I suggest you consider that. Thank you for reading and best wishes to you and your family.


Tues Aug 21 01:55 PM 2007, Ed said:
Doctor, on our 1st trimester baby scan we were told that baby had a 5mm NT (nuchal translucency). We hoped that the consultant could give us some better news on a scan a few days later, but we have the terrible news that it was not simply a wide NT, but a large cystic hygroma of 7mm, extend down the back to the lumbar region. She gave us an 85% chance of choromsome problem and cardiac anomalies even if normal. Also of possible intrauterine death. We are choosing to terminate, we can't wait in hope for a CVS or amniocentesis that MAY indicate the baby is chromosomally normal because it is more likely abnormal. But we have terrible guilt in termination too, as the baby seems ok at the moment. From what I read on the internet, there is a glimmer of hope that the babies do turn out normal. Is this just crazy hope or not?Ed


Wed Aug 22, 04:55:00 PM 2007 Kenneth F. Trofatter, Jr., MD, PhD said...
Although the prognosis is poor, there is always a "glimmer of hope." With your ambivalence and guilt related to pregnancy termination, why don't you have the CVS done and wait just a couple of days. Most labs can give you an answer in as little as 72 hours if they do a "direct prep" for the more common chromosomal abnormalities found with cystic hygromas. If the baby ends up being chromosomally normal, or has a potentially viable condition such as Turner's syndrome, the "glimmer" may improve if the baby survives the first part of the pregnancy....and even if it is chromosomally normal and succumbs, you can walk away having given it the "best shot" and it sounds like that is important for you. Just a thought. Good luck to both of you.


Dr T

Labels: amniocentesis, aneuploidy, CVS, cystic hygroma, first trimester screening

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Percutaneous Umbilical Blood Sampling (PUBS)

In several previous posts, we addressed issues related to invasive diagnostic fetal testing, covering amniocentesis (early and midtrimester) and chorionic villus sampling. I got side-tracked by the ACOG Meeting in San Diego and just remembered that we had never gotten around to a discussion of the other common (though much less so than amniocentesis or CVS) invasive (and at times, therapeutic) procedure, percutaneous umbilical blood sampling (PUBS), otherwise known as cordocentesis or funipuncture.

This, quite simply (but technically tricky), involves the placement of a needle into the umbilical vein to remove fetal blood for a variety of testing purposes such as: chromosomal analysis; genetic studies; hemoglobin analysis (hemoglobinopathies); fetal anemia; platelet count; assessment of fetal acid-base status; fetal infection; coagulation system abnormalities; immune deficiencies. It is commonly used when rapid (48-72hr) and precise fetal chromosomal studies are indicated; in the definitive assessment of anemia under conditions of isoimmunization or parvovirus infection (and as a route of intrauterine transfusion if anemia is confirmed); in the evaluation of thrombocytopenia (= low platelets) resulting from either autoimmune or alloimmune (analogous to Rh-disease) conditions; in the evaluation of fetal hydrops; and, in the confirmation of fetal infections.

PUBS is performed under aseptic conditions and direct ultrasound guidance, much like amniocentesis. Without going into great detail, a slightly larger bore needle is often used than that used with amniocentesis, especially if the procedure is being done for suspected fetal anemia and a transfusion via intravenous access is warranted. When technically feasible, we prefer to access the umbilical vein within 1-2 cm of its placental insertion site. Unlike with amniocentesis, many of us actually prefer to go through the placenta to get to this site. This provides a more stable site for insertion than free cord floating around in the amniotic fluid, improves the prospects for success and probably reduces the risks of the procedure. (Fetal blood sampling can at times also be done directly from the baby, the most common sampling sites being the intrahepatic vein and the fetal heart, but special preparations and precautions must be taken under these circumstances and do not warrant discussion herein).

Although at times the fetal condition might justify earlier evaluation, most fetal blood sampling procedures are done in babies that are 23 weeks or beyond. Since we now consider almost all babies at this gestational age potentially viable, it is recommended that the procedure be performed at an institution that can handle extremely premature babies, and/or babies that may be compromised by the medical condition that led to the PUBS, and at a location in which an emergency cesarean section can readily be performed if a complication arises during or in the immediate post-procedure period.

The most common complications include fetal bradycardia (slow heart rate) during the procedure, hemorrhage or obstructing blood clot at the needle insertion site, and intrauterine infection. Fetal bradycardia is often transient and its mechanism is unclear, but it may be related to spasm in the muscles of the uterine arteries if these were inadvertently punctured during the procedure. Prolonged bradycardia is more common, and more ominous, if it occurs when a baby is severely anemic, hypoxic, acidotic, hydropic (in heart failure), or is hemorrhaging uncontrollably from either the umbilical vein or an umbilical artery. If this cannot be corrected by our typical intrauterine resuscitative measures, immediate delivery may be indicated if the baby is at a gestational age where viability is possible.

Significant fetal hemorrhage from the needle insertion site is a relatively uncommon event; however, it is more likely to occur when the baby has low platelets as may be found in autoimmune, alloimmune, or parvovirus-induced thrombocytopenia. Of these, the greatest risk is in alloimmune thromobocytopenia because the platelet counts are often dangerously low and the platelets that are present may not function normally in clot formation. Babies affected by alloimmune thrombocytopenia are also at great risk for intracranial hemorrhage remote from the labor and delivery process.

In my experience, introduction of infection at the time of the procedure, either from maternal skin bacteria or blood borne organisms such as HIV, CMV, and hepatitis viruses, is a very uncommon event. Rupturing fetal membranes also occurs infrequently, but slightly more often than with amniocentesis alone. Risks for any of these complications rises with the length and complexity of the procedure, the larger the bore of needle used, and maternal obesity.
There are theoretical risks of PUBS to the mother such as causing sensitization to fetal blood cells or platelets, causing damage to internal organs, introducing infection, or causing bleeding, but these are also very uncommon. Probably the greatest risk is that of an emergency cesarean section if this is required to manage a fetal complication.

Procedure-related fetal loss rate is difficult to ascertain but is probably in the range of 1-2% and again is related to the complexity of the procedure and the fetal problem that led to the procedure being recommended in the first place. Babies with an indication for PUBS may be critically ill and, for example, those with hydrops, especially nonimmune hydrops, may not be salvageable regardless of any interventions attempted. It is difficult to consider a loss of one of these babies to be a ‘procedure-related event’ when their morbidity is so high at the outset.

PUBS is the riskiest and most challenging of the more common invasive diagnostic procedures we perform, but it is usually reserved for the most severe fetal compromise as well. In recent years, one of the more common indications for PUBS, screening for fetal anemia, has been replaced by the noninvasive Doppler flow assessment of peak systolic velocity in the fetal middle cerebral artery. PUBS is now only done under these circumstances when a significant fetal anemia is suggested by an abnormal Doppler flow result. Also, with the recent advances in genetic and molecular technologies, many of the studies that required PUBS in the past can be performed simply on amniotic fluid and/or the cells contained within it. And, quite likely, many of these studies will be able to be performed on the small amounts of fetal cells and DNA contained in maternal blood specimens as these technologies continue to advance, further reducing the need for these invasive studies.

Labels: amniocentesis, CVS, isoimmunization, percutaneous umbilical blood sampling, PUBS

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Chorionic Villus Sampling

In the last several posts, I have discussed amniocentesis as a means of fetal diagnosis for chromosomal or genetic problems. Amniocentesis is considered to be an ‘invasive diagnostic procedure.’ We actually have to stick a needle through the fetal membranes (chorion and amnion) and into the sac surrounding the baby to obtain the fluid and cells we need to perform the diagnostic studies. Another common ‘invasive’ procedure we perform is chorionic villus sampling, or CVS. This procedure can best be thought of as a placental biopsy, sampling fetal placental tissues that lie outside the amniotic cavity. It is usually performed during the latter part of the first trimester (10-13 weeks) for reasons I will discuss later on, but actually is a procedure that can be done anytime, preferably, after 10 weeks, when technically feasible, and may be the procedure of choice when fetal chromosomal or genetic studies are indicated and there is little or no fluid surrounding the baby.

Like amniocentesis, we perform CVS under direct ultrasound visualization or ‘guidance.’ The procedure can be done transcervically or transabdominally and the route that is selected is determined by the position of the cervix and uterus and, most importantly, the placental location. When conditions are favorable for CVS to be done transcervically, the perineum, vagina, and cervix are first ‘prepped’ with an antiseptic solution such as povidone-iodine. The cervix is then grasped with an instrument such as a tenaculum that, with gentle traction, can be used to straighten the cervical canal, aligning the cervical canal and the uterine cavity. A catheter containing a semi-rigid stylet is then placed through the cervix to just inside the junction of the cervix and uterus. Then, using ultrasound to follow the path of the catheter tip, it is advanced until positioned beneath the placenta. The stylet is then removed, a syringe is attached to the catheter, and the catheter slowly withdrawn as negative pressure is applied with the syringe. Placental villi can be readily identified as feathery tissue in the tissue culture fluid. In the laboratory, the fetal chromosomal studies can be done by both direct preparations and tissue culture with results available within 3-4 days and 6-10 days, respectively. More cells are usually obtained by CVS than amniocentesis and the cells are usually more metabolically active, allowing a more rapid turn-around time for both chromosomal and biochemical analyses.

If the placenta is not in an accessible location for a transcervical CVS, the transabdominal route may be considered. In many ways, when the placental location lends itself to this approach, it is and often less uncomfortable procedure for the patient. This is also done under aseptic conditions and direct ultrasound guidance. Usually a 19 or 20 gauge spinal needle is used and, because of the large caliber needle, local anesthesia is generally injected at the needle insertion site. Once the needle is positioned under the placenta, a syringe is used to aspirate a sample of villi just as in the transcervical approach.

Although CVS can be done earlier in the pregnancy than amniocentesis, thereby providing results sooner, it is not without risks. Based on early studies, we have generally quoted patients an ‘excess loss rate (= background loss rate minus the procedure-related rate)’ related to CVS of about 1%, or twice the oft-quoted 1 in 200 risk of an amniocentesis later in pregnancy, a number also based on earlier studies. However, as is now the case with amniocentesis, more recent studies have shown that the risk of CVS has decreased with time and, especially, with the experience of the operators. Caughey and colleagues (Obstet Gynecol 2006;108:612-16) recently published a review of 20 years’ experience (1983-2003) with CVS (9,886 procedures) and amniocentesis (30,893 procedures) at a single institution. They found that while the risk of CVS was 4-fold that of amniocentesis over the entire time period, in the recent years between 1998 and 2003, the risks of the two procedures were equivalent and estimated to be about 1 in 370. The results from the FASTER trial, cited previously in our discussion of amniocentesis, also suggest the risk of CVS is only about 1 in 360, but when compared to that study’s results for amniocentesis (risk of 1 in 1600), CVS is still 4-fold riskier for losing a baby as a consequence of the procedure.

Immediate complications of CVS such as bleeding, rupture of membranes, and introduction of infection are surprisingly rare. However, as with early amniocentesis, other consequences of CVS were found during our early experience with the procedure. In 1991, Firth and colleagues reported 5 cases of limb reduction abnormalities among 289 CVS pregnancies (Lancet 1991;337:762-3), 4 of which were associated with ‘oromandibular hypogenesis (basically poor development of the lower face).’ Since the background risk of this complex of abnormalities is approximately only 1 in 175,000 live births, these findings following CVS were considered to be quite significant. Interestingly, all of these abnormalities occurred after transabdominal CVS procedures performed between gestational ages of 55 and 66 days. To make a long story short, the general consensus today is that there is not a significant risk of limb-reduction defects when CVS is performed between 10-13 weeks, but that the risk may be as high as 1-2% if done prior to this time, particularly when done in the 6 to 9 week time period (Jenkins and Wapner. Semin Perinatol 1999;23:403-13).

The only other issue that we typically discuss with women before they undergo CVS relates to the accuracy of the diagnosis. Vejerslev and Mikkelsen reported a 1% frequency of chromosomal mosaicism in CVS specimens (Prenat Diagn 1989;9:575-88). Chromosomal mosaicism indicates two (or more) populations of chromosomally divergent (different) cells, generally, those that are chromosomally normal and those that are not. A baby can have ‘generalized chromosomal mosaicism,’ thought to arise from a mutational event that occurs during the early divisions of the fertilized egg, and have all (or most) body tissues affected. While generalized mosaicism is a relatively rare event, it appears that similar mutations, occurring in the cells that are destined only to become the placental tissues, is not infrequent at all and when this occurs it is defined as “confined placental mosaicism (CPM).”

When mosaicism is found in a CVS specimen, it is recommended that another invasive diagnostic study, either amniocentesis or percutaneous umbilical blood sampling (yet, another post) be performed to rule out generalized fetal mosaicism. However, even if it appears that this is ruled out (there is still a small chance the baby could have a more limited distribution of mosaicism with fewer tissues involved), the finding of CPM still may indicate a pregnancy ‘at risk’ for complications related to placental ‘insufficiency’, including fetal loss, intrauterine growth restriction, and pregnancy-induced hypertensive disorders. Life is never as simple as it seems, is it?!?

Labels: amniocentesis, ChorionicVillusSampling, CVS

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Early Amniocentesis

I was discussing the content of my recent posts (April 17, 2007; April 28, 2007) about amniocentesis with one of my patients today. She was trying to decide between the options for aneuploidy screening and actual fetal chromosomal diagnosis, and the question arose regarding the current status of ‘early amniocentesis’ as an alternative to chorionic villus sampling (which we will be discussing herein sometime over the next couple of days). At the time of today’s visit she was about 12 weeks and was being seen because she will be 43 years old when she is due to deliver. At her age, the risk of delivering a baby with a chromosomal abnormality is about 1 in 40 for trisomy 21 (Down syndrome) and 1 in 31 for all chromosomal abnormalities. The chance of the baby being chromosomally abnormal in first trimester is even higher, 1 in 24 and 1 in 13, respectively. At the outset of our discussion, she was “pretty sure I want a diagnostic study done,” but also didn’t “want to place this pregnancy at any greater risk than necessary” by an invasive procedure since it was her “partner’s first child and I am not getting any younger.”

Most ‘genetic amniocentesis’ procedures are done at 15-18 weeks gestation. The relatively low risks at this point in the pregnancy have been well-documented as discussed in my previous posts. Different folks have different criteria for what they consider to be an ‘early amniocentesis’, I have always defined it to be any amniocentesis done prior to 14 weeks (while the pregnancy is still in the first trimester). We first started doing these about 20-odd years ago at a time when ultrasound technology had improved to the point that we could perform the amniocentesis under ‘direct, real-time, ultrasound guidance.’ Our naïve assumption at the time was that since the procedure seemed to be relatively safe in midtrimester, now that we could see better, it should be just as safe earlier in pregnancy.

Early amniocentesis turned out not only to be technically more difficult than expected, but also less reliable in terms of getting a final fetal chromosome result, and riskier to the pregnancy. I know one of the problems I frequently encountered was difficulty in penetrating the membranes surrounding the baby. The ‘bag of waters’ is actually composed of two layers of membranes, the amnion (closest to the baby) and the chorion. During the first part of the pregnancy, the amnion and the chorion are separated and may not fuse into one sac until the end of the first trimester, and even then, the ‘fusion’ can be weak until later in midtrimester (and sometimes remains that way if a baby has a chromosomal abnormality such as trisomy 21). It was not at all unusual during an attempt at early amniocentesis to see ‘tenting’ of the membranes (separation from each other or from the wall of the uterus) as we tried to push the needle into the space around the baby. When chorionic villus sampling (CVS) came along, providers gravitated to offering that in first trimester and amniocentesis at 15+ weeks rather than performing early amniocenteses routinely.

The only study I am aware of that has actually systematically looked at early amniocentesis was done in Canada (Canadian Early and Mid-Trimester Amniocentesis Trial (CEMAT) Group) published in 1998 (Lancet 1998;351:242-47). In this trial, 4,374 women were randomized to either early amniocentesis (between 11 and 12 6/7 weeks) or midtrimester amniocentesis (between 15 and 16 6/7 weeks). This and subsequent reports from the trial demonstrated that compared to midtrimester amniocentesis, early amniocentesis was associated with a 4-fold risk of a technically difficult (twice the risk of requiring multiple needle insertions) or unsuccessful procedure (1.6% vs. 0.4%), a 10-fold risk of chromosome culture failure (2.4% vs. 0.25%), a higher rate of fluid leakage following the procedure (3.5% vs. 1.7%), a greater risk for pregnancy losses (7.6% vs. 5.9%), and a significantly higher risk (1.3% vs. 0.1%) of having a baby with talipes equinovarus (club foot). Unfortunately, this study did not provide data for amniocenteses done between 13-14 6/7 weeks (when I did most of my ‘early amniocenteses’), but it is doubtful at this point, in view of the results of the CEMAT trial, that this study ever will be done. Today, when a patient requests an earlier diagnosis, but is reluctant to undergo CVS, I will still offer an ‘early amniocentesis’ but counsel them regarding the increased risks and request that they delay this until 14 weeks.

Anyway, after a nice discussion, my patient today decided she would go with ‘combined first trimester screening’ for aneuploidy and probably wait to have an amniocentesis done until 15-16 weeks, “regardless of whether or not the ‘screening’ test is reassuring.” For now, that is the right decision for her…As I have learned in the past, however, with further information, she might still opt for another approach after she gets back today’s final results! At least she now knows what options are available to her.

Labels: amniocentesis

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Amniocentesis Q & A

Yesterday, I addressed the issue of ‘risk’ related to amniocentesis. I thought I should clarify that there are many different reasons we do an amniocentesis, and there are many different times during a pregnancy when it might be indicated that this be done. 'Risk' varies somewhat by time in the pregnancy and indication, and the outcome of a ‘complication’ can be quite different, depending on the gestational age. In the post yesterday, I was specifically addressing the issue of a ‘genetic amniocentesis’, most commonly done between 15 and 22 weeks to determine the fetal karyotype (chromosomes) and to look for evidence of a known or suspected genetic abnormality (inborn error of metabolism). The ‘risk’ addressed in the FASTER trial cited in the post from yesterday is only the risk of losing a baby (prior to viability) after a genetic amniocentesis has been done in midtrimester.

Whenever a woman is considering a genetic amniocentesis during pregnancy, usually one or more of the questions below are among those on her mind. Although the answer to these will vary by provider, let me give you my typical responses:

· “Do you have to stick the baby?” – No, we try to avoid that by looking with the ultrasound while we are doing the procedure. We are actually going to take some of the fluid (about 2/3 oz) from around the baby. The fluid is mostly fetal urine (“baby pee”) at this point in the pregnancy and it contains cells from the baby that we can then grow in the laboratory to determine the baby’s chromosomes. After we get done, the fluid around the baby will look no different to you and the baby will quickly replace the small amount we have removed.

· “Does it hurt? (usually phrased as “My friend told me this REALLY hurts!?!”)” - Usually it is SO painful that we have to have several large nurses sit on you while I do the procedure! No, seriously, we use a very thin needle, thinner than the one they use to draw blood or start an IV. You will probably not feel it much at all as I go through the skin and you will probably feel a cramp, like a menstrual cramp, when I go into the uterus. I will warn you when I am going to do that. You can have someone hold your hand while I am doing the procedure if you would like. Most folks say when it's over that "it wasn't as bad as I thought it was going to be."

· “Are you going to numb me up?” – I can if you would like, although I usually do not and hardly ever have since we started using these thin needles about 20 years ago. The numbing medicine usually hurts more than the needle stick and I can’t numb the uterus to stop the cramp I told you about. Also, if the baby moves, then I might have to stick you 3 or 4 times rather than just once.

· “What are the risks of the procedure? (usually phrased as “My baby moves a lot, what will happen if he/she gets stuck with the needle?”)” – The risk of losing the baby as a result of the procedure is less than 1 in 1000. Other risks include the possibility of breaking the bag of waters, that may or may not lead to delivery or other complications (which I usually do not discuss unless the patients asks at this point), the risk of introducing infection into the uterus, although this is so rare that we do not use any antibiotics to do this procedure and, to help prevent that, we clean your abdomen off first with an antiseptic solution (cold, wet, and scratchy, runs all over the place - the worst part of the procedure) and use sterile drapes (so please do not try to help me with this procedure), and the risk of bleeding either from the placenta if we have to insert the needle through that to get to the fluid, or from the baby, either because of hitting a fetal-placental blood vessel or the baby’s umbilical cord. Again, we try to avoid the latter events by watching with the ultrasound while we do the procedure; even if we do get some bleeding, which is not uncommon when we go across the placenta, it usually stops very quickly and we will watch it until it does. If you are Rh-negative, we will give you Rh-immune globulin after the procedure to help prevent ‘sensitization’ unless you know the baby’s father is Rh-negative too. (I usually do not discuss the possibility of isoimmunization in general unless the mother is Rh-negative or there is substantial bleeding afterwards). I will also be trying to avoid hitting the baby and plan, intentionally, to place the needle away from the baby’s head, but if the baby does move and hit the needle, I will tell you what part of the baby got hit so that we can follow up after the baby is born. Usually there are no long term consequences of this.

· “If I do this test, will it tell me that I am going to have a normal baby?” – That is not an easy question to answer. Chances are, if the chromosomal studies are normal, and we don’t see any abnormalities of the baby, the odds are in your favor the baby will be ‘normal.’ There are rare circumstances when the baby will have a chromosomal problem that is not picked up by the studies or a genetic problem that we did not know about so that we could look, specifically, for it. Other things can also happen during the pregnancy, unrelated to the amniocentesis that could cause the baby not to be ‘normal’ as well.

· “How long does it take to do? (usually phrased as “How long is that needle going to be in me!?!”)” – It usually takes me longer to clean and drape your abdomen than it does for me to do the procedure. Once the needle is in the uterus, it takes about 30 seconds to draw off the fluid because the needle is so thin.

· “How long before I get the results back (usually phrased as “You mean I am NOT going to find out today if my baby’s alright!?!”)” – If we see nothing wrong with the baby, or if you do not have a risk for a specific chromosomal abnormality, such as Down syndrome or trisomy 18 based on other studies, it usually takes 10 to 14 days to get the final results. We can do a rapid screen called FISH (fluorescent in situ hybridization) for a limited number of specific chromosomal abnormalities if one of these is suspected. The results of FISH are usually back within 72 hours, but it does not screen for all chromosomal abnormalities, so routine cultures are also done and you will still have to wait 10-14 days to be completely reassured. The FISH test is also expensive and may not be covered by your insurance carrier because they look at it as a ‘preliminary test’ result.

· “How many days will I have to stay at bed rest? (usually phrased as “Can you give me a note for work for the next week?”)” – Unless there is a complication of the procedure, you will not have to go home to bed rest. We do recommend that you avoid heavy lifting and other exertional activities today and drink some extra fluids. If you think today will be a problem at work, we will give you a note.

· “What do I look for to suggest a problem” – Leakage of fluid, cramping, pain, bleeding, fever – It is not unusual to have a little cramping over the first 24-48 hours after the procedure and you can take Tylenol, or even a few doses of over-the-counter strength ibuprofen, for this, but if it continues longer than that, or if you develop any of the other problems, you need to let your doctor know.

· “When can we have sex again? (usually this one comes from the partner, and the woman is usually grateful when I jokingly answer “NEVER”)” – I usually recommend that you avoid intercourse for 48-72 hours – wait at least 24 hours after the cramping has gone away.

· “How will I get the results” – We will call you as soon as they come back from the laboratory. Do you want to know for sure if the baby is a boy or a girl?

After we have finished the procedure, I usually ask if there are any more questions, wish them the best on the outcome, and tell them that, hopefully, they won’t need to come back to see me again during the pregnancy!

Labels: amniocentesis

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